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Molecular and Cellular Biology

Yong Shen, MacLean A Bassett, Aishwarya Gurumurthy, Rukiye Nar, Isaac J Knudson, Cameron R Guy, Alex Perez, Russell W Mellen, Masatoshi Ikeda, Mir A Hossain, Suming Huang, Kazuhiko Igarashi, Jörg Bungert
The organization of the five β-type globin genes on chromosome 11 reflects the timing of expression during erythroid development, with the embryonic ε-globin gene located at the 5'end, followed by the two fetal γ-globin genes, and the adult β- and δ- globin genes at the 3'end. Here, we functionally characterized a DNase I hypersensitive site located 4 kb upstream of the Gγ-globin gene (HBG-4kb HS). This site is occupied by transcription factors USF1, USF2, EGR1, MafK, and NF-E2 in the human erythroleukemia cell line K562 and exhibits histone modifications typical for enhancers...
July 16, 2018: Molecular and Cellular Biology
Mikhail I Dobrikov, Elena Y Dobrikova, Matthias Gromeier
The Receptor for Activated C-Kinase (RACK1), a conserved constituent of eukaryotic ribosomes, mediates phosphorylation of eukaryotic initiation factor (eIF) 4G1(S1093) and eIF3a(S1364) by protein kinase C (PKC) βII (M. I. Dobrikov, E. Y. Dobrikova, M. Gromeier, Mol. Cell. Biol., submitted, 2018). RACK1:PKCβII activation drives a phorbol ester-induced surge of global protein synthesis and template-specific translation induction of PKC-Raf-ERK1/2-responsive genes. For unraveling mechanisms of RACK1:PKCβII-mediated translation stimulation, we used sequentially truncated eIF4G1 in co-immunoprecipitation analyses to delineate a set of autoinhibitory elements in the N-terminal unstructured region (surrounding the eIF4E binding motif) and the interdomain linker (within the eIF3 binding site) of eIF4G1...
July 16, 2018: Molecular and Cellular Biology
Mikhail I Dobrikov, Elena Y Dobrikova, Matthias Gromeier
Eukaryotic ribosomes contain the high affinity protein kinase C (PKC) βII scaffold, Receptor for Activated C-Kinase (RACK1), but its role in protein synthesis control remains unclear. We found that RACK1:PKCβII phosphorylates eukaryotic Initiation Factor (eIF) 4G1 at S1093 and eIF3a at S1364. We showed that reversible eIF4G(S1093) phosphorylation is involved in a global protein synthesis surge upon PKC-Raf-ERK1/2 activation and in induction of phorbol ester-responsive transcripts, such as cyclooxygenase-2 (Cox-2) and cyclin-dependent kinase inhibitor (p21Cip1 ), or in 5' 7-methyl guanosine (m7 G) cap-independent enterovirus translation...
July 16, 2018: Molecular and Cellular Biology
Yasar Arfat T Kasu, Samrawit Alemu, Angela Lamari, Nicole Loew, Christopher S Brower
Fragments of the TAR DNA-binding protein-43 (TDP43) are major components of intracellular aggregates associated with amyotrophic lateral sclerosis and frontotemporal dementia. A variety of C-terminal fragments (CTFs) exists with distinct N-termini; however, little is known regarding their differences in metabolism and aggregation dynamics. Previously, we found that specific CTFs accumulate in the absence of the Arg/N-end rule pathway of the ubiquitin proteasome system (UPS) and that their degradation requires Arginyl-tRNA-protein transferase 1 (ATE1)...
July 9, 2018: Molecular and Cellular Biology
Marta Blanch, Jonatan Dorca-Arévalo, Anna Not, Mercè Cases, Inmaculada Gómez de Aranda, Antonio Martínez Yélamos, Sergio Martínez Yélamos, Carles Solsona, Juan Blasi
Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein that crosses the Blood-Brain Barrier, binds to myelin and hence, has been suggested as a putative agent for the onset of multiple sclerosis, a demyelinating neuroinflammatory disease. Recently, Myelin and Lymphocyte protein (MAL) has been identified as a key protein in the cytotoxic effect of Etx, however the association of Etx with the immune system remains a central question. Here, we show that Etx selectively recognizes and kills only human cell lines expressing MAL through a direct Etx-MAL interaction...
July 9, 2018: Molecular and Cellular Biology
Ora Haimov, Urmila Sehrawat, Ana Tamarkin-Ben Harush, Anat Bahat, Anna Uzonyi, Alexander Will, Hiroyuki Hiraishi, Katsura Asano, Rivka Dikstein
Translation initiation of most mRNAs involves m7 G-cap binding, ribosomal scanning and AUG selection. Initiation from a m7 G-cap-proximal AUG can be bypassed resulting in leaky-scanning, except for mRNAs bearing the T ranslation I nitiator of S hort 5'UTR (TISU) element. m7 G-cap-binding is mediated by eIF4E-eIF4G1 complex. eIF4G1 also associates with eIF1 and both promote scanning and AUG selection. Understanding the dynamics and significance of these interactions is lacking. We report that eIF4G1 exists in two complexes, either with eIF4E or with eIF1...
July 9, 2018: Molecular and Cellular Biology
Stanley B DeVore, Coleman H Young, Guangyuan Li, Anitha Sundararajan, Thiruvarangan Ramaraj, Joann Mudge, Faye Schilkey, Aaron Muth, Paul R Thompson, Brian D Cherrington
Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas is unknown. To begin to address these questions, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4 and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor...
July 9, 2018: Molecular and Cellular Biology
Joseph F Cardiello, James A Goodrich, Jennifer F Kugel
Cellular transcriptional programs are tightly controlled but can profoundly change in response to environmental challenges or stress. Here we describe global changes in mammalian RNA polymerase II (Pol II) occupancy at mRNA genes in response to heat shock and after recovery from the stress. After a short heat shock, Pol II occupancy across thousands of genes decreased, consistent with widespread transcriptional repression, whereas Pol II occupancy increased at a small number of genes in a manner consistent with activation...
July 2, 2018: Molecular and Cellular Biology
Miki Umeda, Chiaki Tsunekawa, Satoshi Senmatsu, Ryuta Asada, Takuya Abe, Kunihiro Ohta, Charles S Hoffman, Kouji Hirota
The arrangement of nucleosomes in chromatin plays a role in transcriptional regulation by restricting the accessibility of transcription factors and RNA polymerase II to cis -acting elements and promoters. For gene activation, chromatin structure is altered to an open configuration. The mechanism for this process has been extensively analyzed. However, the mechanism by which repressive chromatin is reconstituted to terminate transcription has not been fully elucidated. We here investigated the mechanisms by which chromatin is reconstituted in the fission yeast fbp1 gene, which is robustly induced upon glucose starvation but tightly repressed under glucose-rich conditions...
July 2, 2018: Molecular and Cellular Biology
Kelsey N Maxwell, Yong Zhou, John F Hancock
Rac1 is a small guanine-nucleotide binding protein that cycles between an inactive GDP-bound and active GTP-bound state to regulate cell motility and migration. Rac1 signaling is initiated from the plasma membrane (PM). Here we used high-resolution spatial mapping and manipulation of PM lipid composition to define Rac1 nanoscale organization. We found that Rac1 in the GTP- and GDP-bound states assemble into non-overlapping nanoclusters, thus Rac1 proteins undergo nucleotide-dependent segregation. Rac1 also selectively interacts with phosphatidic acid (PA) and phosphoinositol (3,4,5)-trisphosphate (PIP3 ), resulting in nanoclusters enriched in these lipids...
July 2, 2018: Molecular and Cellular Biology
Xiongjie Jin, Aijun Qiao, Demetrius Moskophidis, Nahid F Mivechi
Activation of adaptive response to cellular stress orchestrated by heat shock factor 1 (HSF1), which is an evolutionary conserved transcriptional regulator of chaperone response and cellular bioenergetics in diverse model systems, is a central feature of organismal defense from environmental and cellular stress. HSF1 activity induced by proteostatic, metabolic and growth factor signals, is regulated by post-transcriptional modifications, yet the mechanisms, which regulate HSF1 and particularly the functional significance of these modifications in modulating its biological activity in vivo remains unknown...
June 25, 2018: Molecular and Cellular Biology
Carlos Perea-Resa, Michael D Blower
Accurate chromosome segregation is a fundamental process in cell biology. During mitosis, chromosomes are segregated to daughter cells through interactions between centromeres and microtubules in the mitotic spindle. Centromere domains have evolved to nucleate formation of the kinetochore, which is essential for establishing connections between chromosomal DNA and microtubules during mitosis. Centromeres are typically formed on highly repetitive DNA that is not conserved in sequence or size among organisms and can differ substantially between individuals within the same organism...
June 25, 2018: Molecular and Cellular Biology
Hiroki Sekine, Keito Okazaki, Koichiro Kato, Md Morshedul Alam, Hiroki Shima, Fumiki Katsuoka, Tadayuki Tsujita, Norio Suzuki, Akira Kobayashi, Kazuhiko Igarashi, Masayuki Yamamoto, Hozumi Motohashi
Cancer cells often heavily depend on the ubiquitin-proteasome system (UPS) for their growth and survival. Irrespective of their strong dependence on the proteasome activity, cancer cells, except for multiple myeloma, are mostly resistant to proteasome inhibitors. A major cause of this resistance is the "proteasome bounce-back response" mediated by NRF1, a transcription factor that coordinately activates proteasome subunit genes. To identify new targets for efficient suppression of UPS, we explored using immunoprecipitation and mass spectrometry the possible existence of nuclear proteins that co-operate with NRF1 and identified O -GlcNAc transferase (OGT) and Host Cell Factor C1 (HCF-1) as two proteins capable of forming a complex with NRF1...
June 25, 2018: Molecular and Cellular Biology
Courtney J Fleenor, Tessa Arends, Hong Lei, Josefine Åhsberg, Kazuki Okuyama, Jacob Kuruvilla, Susana Cristobal, Jennifer L Rabe, Ahwan Pandey, Thomas Danhorn, Desiree Straign, Joaquin M Espinosa, Søren Warming, Eric M Pietras, Mikael Sigvardsson, James R Hagman
Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Krüppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development via a cell-extrinsic mechanism. Mice with inactivated Zfp521 genes ( Zfp521-/- ) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors...
June 18, 2018: Molecular and Cellular Biology
Bo Zhang, Anna M Butler, Qian Shi, Siyuan Xing, Paul K Herman
P-bodies are liquid droplet-like compartments that lack a limiting membrane and are present in many eukaryotic cells. These structures contain specific sets of proteins and mRNAs at concentrations higher than that in the surrounding environment. Although highly conserved, the normal physiological roles of these ribonucleoprotein (RNP) granules remain poorly defined. Here, we report that P-bodies are required for the efficient completion of meiosis in the budding yeast, Saccharomyces cerevisiae P-bodies were found to be present during all phases of the meiotic program and to provide protection for the Hrr25/CK1 protein kinase, a key regulator of this developmental process...
June 18, 2018: Molecular and Cellular Biology
Shakhawoat Hossain, Hiroaki Iwasa, Aradhan Sarkar, Junichi Maruyama, Kyoko Arimoto-Matsuzaki, Yutaka Hata
RASSF6 is a member of the tumor suppressor Ras-association domain family (RASSF) proteins. RASSF6 is frequently suppressed in human cancers and its low expression is associated with poor prognosis. RASSF6 regulates cell cycle arrest and apoptosis and plays a tumor suppressor role. Mechanistically, RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. However, RASSF6 also induces cell cycle arrest and apoptosis in the p53-negative background, which implies that the tumor suppressor function of RASSF6 does not depend solely on p53...
June 11, 2018: Molecular and Cellular Biology
Jingjing Tang, Jeremy M Frey, Carole L Wilson, Angela Moncada-Pazos, Clémence Levet, Matthew Freeman, Michael E Rosenfeld, E Richard Stanley, Elaine W Raines, Karin E Bornfeldt
Macrophages are prominent cells in acute and chronic inflammatory diseases. Recent studies highlight a role for macrophage proliferation post monocyte recruitment in inflammatory conditions. Using an acute peritonitis model, we identify a significant defect in macrophage proliferation in mice lacking leukocyte transmembrane protease ADAM17. The defect is associated with decreased levels of macrophage colony-stimulating factor-1 (CSF-1) in the peritoneum, and is rescued by intraperitoneal injection of CSF-1...
June 11, 2018: Molecular and Cellular Biology
Mariafausta Fischietti, Ahmet D Arslan, Antonella Sassano, Diana Saleiro, Beata Majchrzak-Kita, Kazumi Ebine, Hidayatullah G Munshi, Eleanor N Fish, Leonidas C Platanias
Although members of the Slfn family have been implicated in the regulation of type I interferon (IFN) responses, the mechanisms by which they mediate their effects remain unknown. In the present study we provide evidence that targeted disruption of Slfn2 gene leads to increased transcription of IFN-stimulated genes (ISGs) and enhanced type I IFN-mediated antiviral responses. We demonstrate that Slfn2 interacts with protein phosphatase 6 regulatory subunit 1 (PPP6R1), leading to reduced type I IFN-induced activation of nuclear factor kappa B (NFĸB) signaling, resulting in reduced expression of ISGs...
June 4, 2018: Molecular and Cellular Biology
Masatoshi Kobayashi, Mitsuru Ohsugi, Takayoshi Sasako, Motoharu Awazawa, Toshihiro Umehara, Aya Iwane, Naoki Kobayashi, Yukiko Okazaki, Naoto Kubota, Ryo Suzuki, Hironori Waki, Keiko Horiuchi, Takao Hamakubo, Tatsuhiko Kodama, Seiichiro Aoe, Kazuyuki Tobe, Takashi Kadowaki, Kohjiro Ueki
Adipocyte differentiation is regulated by various mechanisms, of which the mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by the cell cycle modulators, the precise mechanism remains unclear. N 6 -methyladenosine (m6 A) post-transcriptional RNA modification, whose methylation and demethylation is performed by respective enzymal molecules, has recently been suggested to be involved in the regulation of adipogenesis. Here, we show that an RNA N 6 -adenosine methyltransferase complex consisting of Wilms' tumor 1-associating protein (WTAP), methyltransferase like (METTL) 3 and METTL14 positively control adipogenesis, by promoting cell cycle transition in MCE during adipogenesis...
June 4, 2018: Molecular and Cellular Biology
Louis R Ghanem, Andrew Kromer, Ian M Silverman, Xinjun Ji, Matthew Gazzara, Nhu Nguyen, Gabrielle Aguilar, Massimo Martinelli, Yoseph Barash, Stephen A Liebhaber
Formation of the mammalian hematopoietic system is under a complex set of developmental controls. Here we report that mouse embryos lacking the KH-domain poly(C) binding protein, Pcbp2, are selectively deficient in the definitive erythroid lineage. When compared to wild-type controls, transcript splicing analysis of the Pcbp2-/- embryonic liver reveals accentuated exclusion of an exon (exon 6) that encodes a highly conserved transcriptional control segment of the hematopoietic master regulator, Runx1. Embryos rendered homozygous for a Runx1 locus lacking this cassette exon (Runx1ΔE6) effectively phenocopy the loss of the definitive erythroid lineage in Pcbp2-/- embryos...
June 4, 2018: Molecular and Cellular Biology
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